Alzheimer's Disease (AD) is a degenerative brain disorder presented clinically by progressive loss of memory, cognition, reasoning, judgment, and emotional stability that gradually leads to profound mental deterioration and ultimately death. Individuals with AD exhibit characteristic β-amyloid deposits, i.e. β-amyloid plaques or fibrils, in the brain and in cerebral blood vessels, as well as neurofibrillary tangles in areas of the human brain important for memory and cognitive function, as determined during post-mortem analysis of AD patients' brains.
β-amyloid aggregates of different stages, ranging from fibrils (as seen in β-amyloid plaques), protofibrils, oligomers, amyloid pores, Aβ*56 and AD diffusible ligands (ADDL) are predominantly composed of β-amyloid peptides or fragments of β-amyloid peptides, including those ranging in length from 38-43 residues, i.e., Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-42, Aβ1-43 peptides, and fragments thereof, which are interchangeably referred to herein as AB peptides and Aβ peptides. The amino acid sequences of the Aβ peptides are known and differ only in the amino acids present at the C-terminus. For example, the sequence of the Aβ1-42 and Aβ1-43 differs from that of the Aβ1-40 peptide by the addition of two and three, respectively, amino acids at the carboxyl (COOH) terminus.
Aβ peptide aggregate deposits (e.g., plaques) are also characterized in the brains of individuals with Down's Syndrome (Trisomy 21); mixed dementia, including those with combined AD and Parkinson's disease features and those with Lewy body diseases; cerebral amyloid angiopathy, Hereditary Cerebral Hemorrhage with Beta amyloidosis of the Dutch-Type, homozygotes for the apolipoprotein E4, inclusion body myosities, Niemann-Pick type C disease, and other such disorders.
In addition, there are many other forms of brain and non-brain amyloidosis in which the secondary structures of the amyloid are the same or similar. These amyloidosis include primary amyloidosis made of the amyloid light chain (AL) protein, secondary amyloidosis made of the amyloid-associated (AA) protein, hereditary forms of amyloidosis made of AA protein or amyloid transthyretin (ATTR), hemodialysis associated amyloidosis made of beta2-microglobulin, amyloid seen in diabetes made of islet amyloid polypeptide, prion amyloidosis in all kinds of prion disorders, alpha-synuclein amyloid inclusions in Parkinson's disease, amyloid neuropathy, and all other types of disorders labeled as “amyloidosis” or disorders with amyloid inclusions.
In reference to AD, presently, the prevailing “amyloid hypothesis” for AD holds that Aβ peptide monomers aggregate into self-assembled insoluble fibrillar deposits or plaques, and that these insoluble fibrils or plaque deposits are toxic to neuronal cells and is the pathological cause of AD. This theory was developed based, in part, from post-mortem analysis of AD patients' brain, when large numbers of these fibril or plaque deposits are found.
However, the amyloid hypothesis has been challenged by further clinical observations. For example, neuropathologists often observed a poor correlation between Aβ insoluble fibrils or plaque density with AD severity. Notably, there is poor correlation between the number, location and distribution of β-amyloid deposits in AD patients' brain, and parameter of AD pathology, including degree of dementia and neurodegeneration. More recent studies have suggested that soluble precursor Aβ peptide aggregates (e.g., Aβ oligomers (AβO) and Aβ protofibrils), which ultimately aggregate or “polymerize” to form insoluble Aβ deposits (e.g., plaques), are strong neurotoxins and may be the causative form of Aβ that is responsible for neuronal cell death in AD.
At present there are no effective treatments for preventing, or reversing the progression of Alzheimer's disease and treatment is primarily supportive. Stimulated memory exercises on a regular basis have been shown to slow, but not stop, memory loss. A few drugs, such as tacrine, result in a modest temporary improvement of cognition but do not stop the progression of dementia.
Presently, clinical diagnosis of AD is achieved mostly through clinical criteria evaluation, brain biopsies and post-mortem tissue studies. In particular, the inability to assess amyloid deposition in AD until after death impedes the study of this devastating illness. As it is likely that Aβ aggregation probably occurs long before clinical symptoms are noticeable and early detection and treatment of AD would delay the progression and the appearance of the most severe symptoms of the disease, it is generally recognized in the clinical community that a method of quantifying Aβ peptide aggregate deposits before death is needed both as a diagnostic tool in mild or clinically confusing cases, as well as, in monitoring the effectiveness of therapies targeted at preventing Aβ plaque deposition. Therefore, it remains of utmost importance to develop a safe and specific method for diagnosing AD before death by imaging Aβ peptide aggregate deposits in the brain in vivo.
Currently, there are no commercially available ante-mortem probes for detecting Aβ aggregates. Current research efforts to develop methods for diagnosing Alzheimer's disease ante-mortem in vivo have focused on genetic testing, immunoassay methods, and imaging techniques. It has been a challenge to develop high affinity probe for Aβ peptide aggregates that has low toxicity, can cross the blood-brain barrier, and binds more effectively to AD brain than to normal brain in order to identify AD related Aβ peptide aggregates deposits in brain before a patient's death.
In view of the above, there exists a need in the art for small-molecule therapeutic agents capable of preventing, slowing, or reversing the progression of Alzheimer's disease, such as, agents that block the toxic effects of Aβ peptide aggregates (e.g., AβO) on neuronal cells. Additionally, there exists a need for small-molecule ante-mortem probes for detecting Aβ aggregates that have low toxicity, can cross the blood-brain barrier, and binds with specificity to Aβ peptide aggregates, which can be used an ante-mortem probes for diagnosing AD in a person. The present invention satisfies these needs and provides additional advantages as well.